1. Field of the Invention
A number of tricyclic compounds find use in the treatment of depression. These tricyclic antidepressants include imipramine, desmethylimipramine (desipramine), amitriptyline, nortriptyline, protriptylene, and doxepin. In administering a tricyclic antidepressant, it is frequently necessary to ensure that the blood level of the antidepressant remains within a certain narrow concentration range in order to ensure effective dosage, while avoiding levels which may be toxic or produce undesirable effects. Furthermore, it is often necessary to detect potentially toxic levels of tricyclic antidepressants and their metabolites.
It is therefore desirable to provide a simple and rapid procedure for determining or detecting the levels of tricylic antidepressants in serum or other physiological fluids. The procedure should provide reproducible values and be specific for the tricyclic compounds which are measured. Thus, the procedure must be capable of distinguishing the tricyclic antidepressants from other drugs, which would otherwise give an erroneous result in an assay for the detection of tricyclic antidepressants.
2. Brief Description of the Prior Art
The tricyclic antidepressants are closely related chemically to one another. Techniques reported for the determination of amitriptyline in biological fluids include the use of thin layer chromatography, gas-liquid chromatography and GLC-mass spectrometry. Gifford, et al., J. of Chrom., 105, 107-113 (1975); Gupta, et al., Clin. Biochem., 9, 247-251 (1976); Nyberg and Martensson, J. Chromatography, 143, 491 (1977); Watson and Stewart, J. Chrom., 134, 182 (1977); ibid. 132 155-159 (1977). Radioimmunnoassay has been reported for amitriptyline by Aherne, et al., Br. J. Clin. Pharmac., 3, 561 (1976), Turner, Lancet, 180, 1316 (1977); and Aherne, et al., Lancet 1214 (1977). In Aherne, et al., ibid., a synthesis for an antigen for use as an immunogen for antibody formation is described, where nortriptyline is substituted with aminobutylene followed by conjugation to bovine serum albumin employing carbodiimide. In another antigen conjugate synthesis by Kaul, et al., J. Anal. Tox., 1, 236 (1977), nortiptyline was conjugated to bovine serum albumin through a succinyl group. The resulting antibodies were found to have significant cross-reactivity with a number of other tricyclic drugs.
U.S. Pat. No. 4,275,160 describes imipramine derivatives and poly(amino acid) conjugates. U.S. Pat. Nos. 4,223,013 and 4,307,245 disclose amitriptyline conjugates to antigenic proteins and enzymes.
N-(2-carboxyethyl) derivatives of nortriptyline and desipramine are disclosed by Hubbard et al., J. Pharm. Sc., 67, pp. 1571-1578 (1978) and by Hubbard et al., Canadian Journal of Pharmaceutical Sciences, 15, pp 89-93 (1980).